A method for identification of mixed pseudo- and anti-glucocorticoid disruptors based on enhanced sampling molecular dynamics simulations

An anti-glucocorticoid and glucocorticoid technology, applied in biological testing, material inspection products, etc., can solve problems such as limitations, and achieve the effect of low cost and high efficiency

Active Publication Date: 2020-06-26
NANJING UNIV
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  • Claims
  • Application Information

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Problems solved by technology

[0035] The technical problem to be solved in the present invention is to provide a method for discovering the steady-state conformation of the glucocorticoid receptor based on the enhanced sampling molecular dynamics simulation method, to solve the limitations of existing methods in finding the coexistence phenomenon of multi-stable conformation

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  • A method for identification of mixed pseudo- and anti-glucocorticoid disruptors based on enhanced sampling molecular dynamics simulations
  • A method for identification of mixed pseudo- and anti-glucocorticoid disruptors based on enhanced sampling molecular dynamics simulations
  • A method for identification of mixed pseudo- and anti-glucocorticoid disruptors based on enhanced sampling molecular dynamics simulations

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Experimental program
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Embodiment 1

[0069] Example 1: Molecular dynamics simulation of GR

[0070] The structure of human GR adopts the GR protein structure with PDB code 1m2z in the protein database, and checks the integrity of its structure and repairs the missing residues through the Swiss-PdbViewer software. Ligand small molecules, including standard substances and endocrine disruptor bisphenols commonly found in the environment, are structurally optimized and docked in the receptor using the Surflex-Dock module in SYBYL 7.3 to form a ligand-receptor complex. The complex is subjected to enhanced sampling molecular dynamics simulation using the widely recognized enhanced sampling molecular dynamics simulation method—metadynamics simulation method—and the molecular simulation software used is gromacs and plumed software packages. The distance between I757 and L733, I757 and Q597, and K770 and V675 α-carbon atoms was used as an aggregate variable in the metadynamics simulation process. The simulation time of e...

Embodiment 2

[0071] Embodiment 2: analysis of molecular dynamics simulation results

[0072] The molecular simulation trajectory obtained in Example 1 was used for further analysis. The distance between the carboxyl terminal of GR H12 (amino acids 758-762) and the centers of H3, H4 and H5 (Distance unit is nanometers), and the helicity of H12 (amino acids 749-765) is the α-helix scoring value ( alpha-helix score) are respectively used as CVs to describe the conformational changes of H12 of GR, so as to draw the free energy (Free Energy, unit is kJ / mol) characteristic map, describe the position of H12, obtain the lowest point of global and local free energy, and pass Conformation clustering obtains the representative conformation at the lowest point of free energy, which is the representative steady-state conformation. According to the H12 stable position of the representative steady-state conformation, the type of each steady-state conformation was judged. Finally, according to the type ...

Embodiment 3

[0073] Embodiment 3: the result analysis of standard substance DEX, RU486

[0074] For the DEX of the pure pseudo-standard substance, the metadynamics simulation results show that the steady-state conformation of DEX-GR is a single type of activated conformation ( Figure 2A ), can selectively recruit CoA, which is consistent with the reported crystal structure of DEX-GR. For RU486 of mixed pseudo-resistant compounds, the metadynamics simulation results show that RU486-GR has various types of steady-state conformations, including blocking and competing conformations ( Figure 2B ), so as to not only recruit CoA to lead to mimetic effect, but also inhibit CoA to lead to resistance effect. Therefore, under the action of pure mimetic compounds, GR forms an activated conformation, leading to the selective recruitment of CoA by the receptor, which in turn leads to transcriptional activation and pure mimetic effects. However, mixed mimetic and resistant compounds induce multiple s...

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Abstract

The invention discloses a hybrid mimetic and resistant glucocorticoid interferent identifying method based on enhanced sampling molecular dynamics simulation. Based on a nuclear receptor allosteric and co-regulatory factor regulation mechanism, an enhanced sampling molecular dynamics simulation method is adopted. By identifying the lowest points of local and global free energy and performing dynamic trajectory clustering, the steady-state conformation of a glucocorticoid receptor under the action of ligand compounds is extracted. According to the relationship between the stable position of thereceptor helix 12 and the recruitment / inhibition mechanism of a co-regulatory factor, the endocrine disruption effect of a test compound is determined. Mimetic and resistant and hybrid mimetic and resistant glucocorticoid interferents are identified and predicted. Compared with a traditional in vitro experimental method, the method is cheaper and more efficient, and avoids cell-specific issues with mixed hybrid and resistant interferents. Compared with the existing computer-aided screening method, the method can effectively identify stable conformation, and achieve the prediction of hybrid mimetic and resistant glucocorticoid interference effects.

Description

technical field [0001] The invention belongs to the field of predictive toxicology using computer programs, and in particular relates to nuclear receptor-mediated mimicry, resistance and mixed pseudo-resistance glucocorticoid interferents based on enhanced sampling molecular dynamics simulation using computer software recognition methods. Background technique [0002] Endocrine disrupting chemicals (EDCs) refer to ligand compounds that cause harmful effects by interfering with the endocrine system. EDCs in ambient media 1,2 ,food 3 even human blood 4,5 It has been widely detected, and its exposure will cause a series of impacts on human health, increasing the risk of reproductive diseases 6 , birth defects 7 , prostate and breast cancer 8 , cardiopulmonary disease 9 , obesity 10 and neurological diseases 11 and other risks, and caused huge economic losses. The cost of diseases caused by EDCs in the EU was 217 billion U.S. dollars, accounting for 1.28% of GDP, while ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G01N33/74
CPCG01N33/74
Inventor 史薇陈钦畅于红霞
Owner NANJING UNIV
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